Herein we propose the d-Trp-Phe sequence within an inverse type II b-turn as a new kind of pharmacophoric motif for mopioid receptor (MOR) cyclopeptide agonists. Initially, we observed that c[Tyr-d-Pro-d-Trp-Phe-Gly] (4), an analogue of endomorphin- 1 (H-Tyr-Pro-Trp-Phe-NH2) lacking the crucial protonatable amino group of Tyr1, is a MOR agonist with 108m affinity. Molecular docking analysis suggested that the relevant interactions with the receptor involve d-Trp-Phe. The bioactive conformation of this region was investigated by selected derivatives of 4 designed to adopt an inverse type II b-turn. These efforts led to c[Tyr-Gly-d-Trp-Phe-Gly] (14) and to the cyclotetrapeptide c[d-Asp-1-amide-b-Ala-d-Trp-Phe] (15), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the k- and d-opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse b-turn in binding. These results indicate that the d-Trp-Phe inverse b-turn structure can be used for designing non-endomorphin-like peptidomimetic opioid agonists in general, characterized by an atypical mechanism of interaction between ligand and receptor.

The Inverse Type II β-Turn on D-Trp-Phe, a Pharmacophoric Motif for MOR Agonists.

GENTILUCCI, LUCA;TOLOMELLI, ALESSANDRA;DE MARCO, ROSSELLA;SPAMPINATO, SANTI MARIO;BEDINI, ANDREA;
2011

Abstract

Herein we propose the d-Trp-Phe sequence within an inverse type II b-turn as a new kind of pharmacophoric motif for mopioid receptor (MOR) cyclopeptide agonists. Initially, we observed that c[Tyr-d-Pro-d-Trp-Phe-Gly] (4), an analogue of endomorphin- 1 (H-Tyr-Pro-Trp-Phe-NH2) lacking the crucial protonatable amino group of Tyr1, is a MOR agonist with 108m affinity. Molecular docking analysis suggested that the relevant interactions with the receptor involve d-Trp-Phe. The bioactive conformation of this region was investigated by selected derivatives of 4 designed to adopt an inverse type II b-turn. These efforts led to c[Tyr-Gly-d-Trp-Phe-Gly] (14) and to the cyclotetrapeptide c[d-Asp-1-amide-b-Ala-d-Trp-Phe] (15), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the k- and d-opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse b-turn in binding. These results indicate that the d-Trp-Phe inverse b-turn structure can be used for designing non-endomorphin-like peptidomimetic opioid agonists in general, characterized by an atypical mechanism of interaction between ligand and receptor.
Gentilucci L; Tolomelli A; De Marco R; Spampinato S; Bedini A; Artali R.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/106719
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